The objective of this Program Project is to critically evaluate a hypothesized two-armed cascade of molecular and cellular events that contributes to the pathogenesis of Alzheimer disease. Microglial activation with synthesis and release of interleukin-1 (IL-1) is seminal in this cascade. IL-1-based actions include (i) induction of overexpression and processing of beta-amyloid precursor protein in neurons and overgrown dystrophic neurites (leading to beta-amyloid deposition, which in turn activates complement and promotes calcium channel formation (leading ultimately to cell death); and (ii) activation of astrocytes with synthesis and release of S100beta (increasing the potential for cell death, by promoting increases in intraneuronal calcium, and promoting synthesis of beta-APP by inducing overgrowth of dystrophic neurites) and with synthesis and release of ApoE (which may bind the beta-amyloid and stabilize it). Alzheimer's disease is progressive, and any sequence of events hypothesized to significantly contribute to the pathogenesis of this disease must be progressive. Therefore, we postulate further that the progressive nature of Alzheimer's disease results from a self propagating, self sustaining sequence of events brought about by complement-mediated microglial activation with consequent feedback stimulation of further synthesis and release of interleukin-1. We will determine the regional and topographical distribution of the molecular and cellular components of our proposed cascade and establish interrelationships between these components in AD, in head injury (a risk factor for later development of AD), in critical coronary artery disease (recently shown to be associated with AD-like neuropathological changes), and in epilepsy (a non-dementing chronic neurological disease recently shown to manifest some AD-like glial, cytokine, and neuronal neuropathological changes). As a critical test of the role of glia in this neurodegenerative cascade, experiments will also be performed in glia-depleted animal models. Finally, we will administer glia-derived cytokines in vitro to cells to directly evaluate the cascade-initiating potential of these molecules. This hypothesis has obvious and immediate implication for the therapeutic intervention in the progression of Alzheimer's disease.